The present invention relates to some O-sulfonyl hydroxamic and carboxylic acids displaying potent and selective inhibitory activity against some Matrix MetalloProteinases (MMPs), to their use for the treatment of diseases in which the proteolytic activity of these MMPs is involved, to methods for their preparation, and to pharmaceutical compositions containing them.
Under physiological conditions MMPs play an important role in normal tissue turnover and development. However, increased MMP activity and/or impairment of the physiological MMP inhibitors has been associated with a variety of pathological conditions such as cancer, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, stroke, arteriosclerosis, restenosis and age-related macular degeneration. In cancer, the contribution of MMPs is manifold and not limited to destruction of the extracellular matrix required for local and distal invasion. The proteolytic action of MMPs generates active matrix protein fragments, and influence the release, activation and bioavailability of growth factors. In addition, MMPs are involved in cell migration and in the processing or shedding of cell surface proteins. It is now believed that the proteolytic action of MMPs plays a very important role in tumor growth, apoptosis and angiogenesis (see Noel, A. et al., xe2x80x98Emerging Roles for Proteinases in Cancerxe2x80x99, Invasion Metastasis 17:221-239, 1997). Among the several MMPs known to date, gelatinase-A (MMP-2) is currently reputed as the main target in cancer.
Potent MMP inhibitors (MMPIs) were disclosed three decades ago (e.g., see Dickens, J. P. et al., U.S. Pat. No. 4,599,361), but only recently some of them entered clinical trials, and none has arrived at the market yet. Questions remain concerning their specificity, bioavailability, and potential long-tens toxicity (see Hodgson, J., xe2x80x98Remodeling MMPIsxe2x80x99, Biotechnology 13:554-557, 1995), especially because they are primarily intended (in arthritis and cancer, at least) for prolonged therapy. Marimastat, the most advanced MMPI in the clinic, and other compounds currently investigated in patients such as Novartis CGS27023A and Agouron AG3340, have been reported to cause a musculoskeletal syndrome characterized by joint pain and stiffness, which may be severe and dose-limiting. Although the cause of this toxicity is not well understood at this moment, it is thought to arise from an impairment in the normal tissue remodeling that is governed by one or more of the MMPs, primarily fibroblast collagenase (MMP-1). We have extended these observations by developing an animal model of joint toxicity, involving treatment of rats for 10 days with MMPIs at exposures close to that required for antitumor efficacy in mice (human prostate DU-145 model). In this rat model, MMPIs characterized by poor selectivity (i.e., comparable potency against MMP-2 and MMP-1), such as marimastat and Roche Ro31-9790, elicited histological alteration of stifle joints (hypertrophic fibrosis of ligaments, interstitial hypertrophic fibrosis of skeletal muscles, hypertrophic fibroplasia of the periostium and synovium, chondrodysplasia, and decreased endochondrial ossification of the ephyseal plate); in some cases, clinical symptoms (abnormal posture, reluctance to move, abnormal gait) were also observed. Thus, there is a strong need for better MMPIs, especially as far as the properties referred to above (specificity, bioavailability, long-term toxicity) are concerned. The compounds of the present invention are intended to provide these advantages.
A previous disclosure by the Pharmacia and Upjohn Company, PCT Patent Application WO 98/13340 (U.S. Pat. No. 5,847,153), provides a broad range of xcex2-sulfonyl hydroxamic acid derivatives, their preparation, and their activity against various enzymes of the MMP family, predominantly stromelysin and gelatinase. These compounds are generically described by the formula (Ia): 
wherein R1 is C4-12 alkyl, C4-12 alkenyl, C4-12 alkynyl, xe2x80x94(CH2)hxe2x80x94C3-8 cycloalkyl, xe2x80x94(CH2)h-aryl, or xe2x80x94(CH2)h-het; R2 is C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, xe2x80x94(CH2)hxe2x80x94C3-8 cycloalkyl, xe2x80x94(CH2)hxe2x80x94C3-8 cycloalkenyl, xe2x80x94(CH2)h-aryl, xe2x80x94(CH2)h-het, xe2x80x94(CH2)hxe2x80x94Q, xe2x80x94(CH2)lxe2x80x94Xxe2x80x94R4, or xe2x80x94(CH2)lxe2x80x94CHR5R6.
We have now found that the combination of few particular groups R1 and R2 in a molecule of formula (Ia) provides distinct advantages over the other compounds of this class of MMPIs. Said combination, which is an object of the present invention, is associated with outstanding potency (Ki in the picomolar range) against the gelatinases, in particular MMP-2, and relatively weak activity against fibroblast collagenase (MMP-1). Further, we have found that the same combination confers good potency (low nanoM range) and even higher selectivity for MMP-2 to the corresponding carboxylates, which were previously described as intermediates but not claimed as such. Finally, we have found that the same combination provides advantages in the pharmacokinetic parameters, in particular lower clearance and higher oral bioavailability, and that antitumor efficacy in rodents can be achieved in the absence of joint toxicity.
The present invention provides 3-arylsulfonyl-2-methyl propanoic acid derivatives of formula (I): 
or pharmaceutically acceptable salts thereof wherein:
X is either HOxe2x80x94NHxe2x80x94 (hydroxamic acids) or HOxe2x80x94 (carboxylic acids);
R1 is selected from phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, benzamido (i.e., xe2x80x94NHxe2x80x94CO-Ph) or benzamido substituted on the terminal Ph ring by C1-4 alkyl, fluoro, chloro, cyano, C1-4 alkoxy;
R2 is selected from:
(a) xe2x80x94Sxe2x80x94Ar or xe2x80x94Sxe2x80x94CH2xe2x80x94Ar, wherein Ar is a monocarbocyclic or bicarbocyclic aromatic moiety, preferably phenyl, naphthyl and biphenyl, which is either unsubstituted or substituted with one or two substituents selected from the group consisting of C1-4 alkyl, phenyl, benzyl, C1-4 alkoxy, fluoro, chloro, bromo, nitro, cyano, hydroxy, amino, dimethylamino, acetamido, methylthio and acetyl;
(b) Oxe2x80x94Ar, wherein Ar is as defined above;
(c) xe2x80x94S-Het or xe2x80x94Sxe2x80x94CH2-Het, wherein Het is a heterocyclic ring selected from the group consisting of pyridine, pyrimidine, pyridazine, pyrazine, 1,2,5-triazine, imidazole, thiophene, furan, pyrrole, pyrazole, 1,3-thiazole, 1,3-oxazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole, 1,3,4-oxadiazole, 1,2,3,4-tetrazole, quinoline, isoquinoline, indole, 1,3-benzoxazole, 1,3-benzothiazole, benzimidazole, [1,3]oxazolo[4,5-b]pyridine, [1,3]thiazolo[4,5-b]pyridine, [1,2,3,4]tetrazolo[1,5-b]pyridazine and purine, and wherein said Het group can be substituted with one to three substituents selected from the group consisting of C1-4 alkyl, phenyl, pyridyl, benzyl, C1-4 alkoxy, methylthio, fluoro, chloro, nitro, cyano, hydroxy, oxo, amino, methylamino, dimethylamino, 2-dimethylaminoethyl, acetamido and acetyl;
(d) 2,5-dioxo-1-imidazolidinyl or 2,4-dioxo-1-imidazolidinyl, which can be substituted at the carbon atom with one or two methyl groups, or with C2-4 linear or branched alkyl, phenyl, benzyl or hydroxymethyl, and at the nitrogen atom with C1-4 linear or branched alkyl.
The compounds of the present invention can be converted to pharmaceutically acceptable salts, where appropriate, according to conventional methods. The term xe2x80x98pharmaceutically acceptable saltsxe2x80x99 refers to acid addition salts useful for administering the compounds of this invention and includes hydrochloride, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citrate, 2-hydroxyethyl sulfonate, fumarate and the like. Alternatively, the compounds of this invention, especially when X in formula (I) is hydroxy, may form metal salts, such as sodium, potassium, calcium or magnesium, or ammonium salts, or salts with an appropriate organic amine or amino acid such as arginine, procaine and the like. Any salt may be either in the anhydrous or hydrated form, or may be solvated with acceptable solvents, such as ethanol.
The present invention also provides pharmaceutical compositions which comprise, as active ingredient, a compound of formula (I) or a solvate, hydrate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
The compounds of this invention contain a chiral center at the xcex1-position of the hydroxamic or carboxylic acid, and as such they may be obtained as any of the two separate enantiomers or as a racemic mixture of both. Preferred compounds of this invention are either the racemates or individual isomers having the configuration depicted in the formula (Ixe2x80x2) herebelow: 
wherein X, R1 and R2 are as defined above. According to the Cahn-Ingold-Prelog rule, these preferred isomer are denoted as (R) when R2 is Oxe2x80x94Ar, 2,5-dioxoimidazolidin-1-yl or 2,4-dioxoimidazolidin-1-yl, and as (S) when R2 is xe2x80x94Sxe2x80x94Ar, S-Het, xe2x80x94Sxe2x80x94CH2xe2x80x94Ar or xe2x80x94Sxe2x80x94CH2-Het. In addition, depending on the substituents, additional chiral centers or other isomeric forms may be present, and this invention embraces all possible stereoisomers and geometrical forms.
Particularly preferred compounds of this invention are as follows:
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(phenylsulfanyl)methyl]propanoic acid;
(2S)-3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(phenylsulfanyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(phenylsulfanyl)methyl]-propanamide;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]yl)sulfonyl]-2-[[(4-hydroxyphenyl)sulfanyl]methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[[(4-hydroxyphenyl)sulfanyl]-methyl]propanamide;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-(phenoxymethyl)propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-(phenoxymethyl)propanamide;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(2-pyridinylsulfanyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(2-pyridinylsulfanyl)methyl]-propanamide;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[(2-pyridinylmethyl)sulfanyl]methyl]-propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[[(2-pyridinylmethyl)sulfanyl]methyl]propanamide;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]-methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl]propanamide;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[(5-amino-1,3,4-thiadiazol-2-yl)-sulfanyl]-methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[(1-methyl-1H-imidazol-2-yl)sulfanyl]methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(2-pyrimidinylsulfanyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[(1-methyl-1H-tetrazol-5-yl)sulfanyl]methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[(1-benzyl-1H-tetrazol-5-yl)sulfanyl]methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(1H-benzimidazol-2-ylsulfanyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(1,3-thiazol-2-ylsulfanyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[(2-methyl-2H-1,2,3-triazol-4-yl)sulfanyl]-methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[(5-phenyl-1,3 ,4-oxadiazol-2-yl)sulfanyl]-methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[[1-(3-pyridinyl)-1H-imidazol-2-yl]sulfanyl]methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[(4-methyl-1,3-oxazol-2-yl)sulfanyl]methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[([1,3]oxazolo[4,5-b]pyrimidin-2-yl-sulfanyl)methyl]propanoic id;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[([1,2,3,4]tetrazolo[1,5-b]pyridazin-6-yl-sulfanyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[(2,6-dimethylpyrimidinyl)sulfanyl]-methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[(4,6-dimethyl-2-pyrimidinyl)sulfanyl]methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[(4-hydroxy-6-methyl-2-pyrimidinyl)sulfanyl]methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[(4,6-dihydroxy-2-pyrimidinyl)sulfanyl]methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(9H-pufin-6-ylsulfanyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-(3-fluorophenoxymethyl)propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(2-acetylaminophenoxy)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(4-acetylaminophenoxy)methyl]propanoic acid;
3-([1,1xe2x80x2-Biphenyl]-4-ylsulfonyl)-2-[(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)methyl]-propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)methyl]propanoic acid;
(2R)-3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)methyl]propanamide;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)methyl]propanamide;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(2,5-dioxo-1-imidazolidinyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(2,5-dioxo-1-imidazolidinyl)methyl]propanamide;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(3-methyl-2,5-dioxo-1-imidazolidinyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(3-ethyl-2,5-dioxo-1-imidazolidinyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-ylsulfonyl]-2-[(3-butyl-2,5-dioxo-1-imidazolidinyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(3-butyl-2,5-dioxo-1-imidazolidinyl)methyl]propanamide;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(3-butyl-2,4-dioxo-1-imidazolidinyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(3-butyl-2,4-dioxo-1-imidazolidinyl)methyl]propanamide;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(5-isopropyl-2,4-dioxo-1-imidazolidinyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(5-hydroxymethyl-2,4-dioxo-1-imidazolidinyl)methyl]propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(5-hydroxymethyl-3-methyl-2,4-dioxo-1-imidazolidinyl)methyl]propanoic acid;
3-[(4xe2x80x2-Fluoro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(phenylsulfanyl)methyl]propanoic acid;
3-[(4xe2x80x2-Fluoro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(phenylsulfanyl)methyl]propanamide;
3-[(4xe2x80x2-Fluoro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-(phenoxymethyl)propanoic acid;
3-[(4xe2x80x2-Fluoro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-(phenoxymethyl)propanamide;
3-[(4xe2x80x2-Cyano[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(phenylsulfanyl)methyl]propanoic acid;
3-[(4xe2x80x2-Cyano[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(phenylsulfanyl)methyl]propanamide;
3-[(4xe2x80x2-Cyano[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-(phenoxymethyl)propanoic acid;
3-[(4xe2x80x2-Cyano[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-phenoxymethyl)propanamide;
3-[(4xe2x80x2-Cyano[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-(3-fluorophenoxymethyl)propanoic acid;
3-[(4xe2x80x2-Cyano[1,1xe2x80x2-biphenyl]-4-yl )sulfonyl]-2-[(2-acetylamino)phenoxymethyl]propanoic acid;
3-[(4xe2x80x2-Cyano[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(2-pyridinylsulfanyl)methyl]propanoic acid;
3-[(4xe2x80x2-Cyano[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[(2-pyridinylmethyl)sulfanyl]methyl]propanoic acid;
3-[(4xe2x80x2-Cyano[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(3-butyl-2,5-dioxo-1-imidazolidinyl)methyl]propanoic acid;
3-[(4xe2x80x2-Cyano[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-N-hydroxy-2-[(3-butyl-2,5-dioxo-1-imidazolidinyl)methyl]propanamide;
3-[(4xe2x80x2-Cyano[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[(5-hydroxymethyl-2,4-dioxo-1-imidazolidinyl)methyl]propanoic acid;
3-[[4-(Benzoylamino)phenyl]sulfonyl]-2-[(phenylsulfanyl)methyl]propanoic acid;
3-[[4-(Benzoylamino)phenyl]sulfonyl]-N-hydroxy-2-[(phenylsulfanyl)methyl]propanamide;
3-[[4-(Benzoylamino)phenyl]sulfonyl]-2-[[(2-pyridinylmethyl)sulfanyl]methyl]propanoic acid;
3-[[4-(Benzoylamino)phenyl]sulfonyl]-2-[(2-thienylsulfanyl)methyl]propanoic acid;
3-[[4-(Benzoylamino)phenyl]sulfonyl]-2-(phenoxymethyl)propanoic acid;
3-[[4-[(4-Methylbenzoyl)amino]phenyl]sulfonyl]-2-[(phenylsulfanyl)methyl]propanoic acid;
3-[[4-[(4-Methylbenzoyl)amino]phenylsulfonyl]-N-hydroxy-2-[(-phenylsulfanyl)methyl]propanamide;
3-[[4-[(4-Chlorobenzoyl)amino]phenyl]sulfonyl]-2-[(phenylsulfanyl)methyl]propanoic acid;
3-[[4-[(4-Chlorobenzoyl)amino]phenyl]sulfonyl]-N-hydroxy-2-[(phenylsulfanyl)methyl]propanamide;
3-[[4-[(4-Chlorobenzoyl)amino]phenyl]sulfonyl]-2-(phenoxymethyl)propanoic acid;
3-[[4-[(4-Chlorobenzoyl)amino]phenyl]sulfonyl]-N-hydroxy-2-(phenoxymethyl)propanamide;
3-[[4-[(4-Clorobenzoyl)amino]phenyl]sulfonyl]-2-(3-fluorophenoxymethyl)propanoic acid;
3-[[4-[(4-Chlorobenzoyl)amino]phenyl]sulfonyl]-2-[[(2-pyridinylmethyl)sulfanyl]methyl]propanoic acid;
3-[[4-[(4-Chlorobenzoyl)amino]phenyl]sulfonyl]-2-[[(1-methyl-1H-tetrazol-5-yl)sulfanyl]methyl]propanoic acid;
3-[[4-[(4-Chlorobenzoyl)amino]phenyl]sulfonyl]-2-[(5-hydroxymethyl-2,4-dioxo-1-imidazolidinyl)methyl]propanoic acid;
3-[[4-[(4-Cyanobenzoyl)amino]phenyl]sulfonyl]-2-[(phenylsulfanyl)methyl]propanoic acid;
3-[[4-[(4-Cyanobenzoyl)amino]phenyl]sulfonyl]-N-hydroxy-2-[(phenylsulfanyl)methyl]propanamide;
3-[[4-[(4-Cyanobenzoyl)amino]phenyl]sulfonyl]-2-[[(1-methyl-1H-tetrazol-5-yl)sulfanyl]methyl]propanoic acid;
3-[[4-[(4-Cyanobenzoyl)amino]phenyl]sulfonyl]-2-(phenoxymethyl)propanoic acid;
3-[[4-[(4-Cyanobenzoyl)amino]phenyl]sulfonyl]-N-hydroxy-2-(phenoxymethyl)propanamide;
3-[4-[(4-Cyanobenzoyl)amino]phenyl]sulfonyl]-2-(3-fluorophenoxymethyl)propanoic acid;
3-[[4-[(4-Cyanobenzoyl)amino]phenyl]sulfonyl]-N-hydroxy-2-(3-fluorophenoxymethyl)propanamide;
3-[[4-[(4-Cyanobenzoyl)amino]phenyl]sulfonyl]-2-[(2-acetylamino)phenoxymethyl]propanoic acid;
3-[[4-(4-Propylbenzoylamino)phenyl]sulfonyl]-2-[[(1-methyl-1H-tetrazol-5-yl)sulfanyl]methyl]propanoic acid;
3-[[4-[(4-Methoxybenzoyl)amino]phenyl]sulfonyl]-2-(phenoxymethyl)propanoic acid;
3-[(4xe2x80x2-Chloro[1,1xe2x80x2-biphenyl]-4-yl)sulfonyl]-2-[[2-(hydroxymethyl)phenoxy]methyl]propanoic acid.
The compounds of this invention can be prepared by a process starting from a compound of formula 4: 
wherein R is H or the residue of a carboxylic acid ester, R1 and R2 are as defined above and n is 0 or 2, which process comprises:
(a) hydrolysing a said compound of formula 4 in which R is the residue of a carboxylic and ester to give a compound of formula (I) in which X is HOxe2x80x94; or
(b) hydrolysing and oxidising, in either order, a said compound of formula 4 in which n is 0 and R is the residue of a carboxylic acid ester, to give a compound of formula (I) in which X is HOxe2x80x94; or
(c) activating a said compound of formula 4 wherein R is H and n is 2 to form an activated carboxy group, coupling the activated carboxy group with hydroxylamine or an O-protected derivative thereof and, if necessary, deprotecting the hydroxamic group to give a compound of formula (I) wherein X is xe2x80x94NHOH; or
(d) submitting a said compound of formula 4 wherein R is H and n is zero to a sequence of reactions comprising oxidation at the sulphur atom, activation of the carboxy group, condensation of the activated carboxy group with hydroxylamine or an O-protected derivative thereof and, if necessary, deprotection of the hydroxamic group to form a compound of formula (I) wherein X is xe2x80x94NHOH, the oxidation step being conducted either before the activation step or after the condensation step; and/or
(e) if desired, converting a resulting compound of formula (I) into another compound of formula (I); and/or converting a free compound into a pharmaceutically acceptable salt thereof; and/or converting a salt into a free compound.
The compound of formula 4 may be obtained by
(a) subjecting a compound of formula 2: 
wherein R, R1 and n are as defined above, to conjugate addition by treatment with a compound of formula R2H wherein R2 is as defined above; or
(b) treating a compound of formula 3: 
wherein R and R2 are as defined above, with a thiol of formula: 
to obtain a compound of formula 4 in which n is zero.
These processes are depicted in the following Scheme 1, where R1 and R2 are the groups as defined previously, R is either a hydrogen atom or the residue of a carboxylic ester such as methyl, ethyl, n-butyl, tert-butyl, benzyl or benzhydryl, and n is either zero or 2. Compound 1, i.e. 2-(bromomethyl)acrylic acid or an ester thereof, is reacted with the appropriate aryl-thiol in a suitable solvent such as toluene or dimethylformamide (DMF) in the absence or presence of a suitable base such as sodium bicarbonate or triethylamine TEA), at ambient temperature or under heating up to reflux temperature, to afford a compound 2 wherein n is zero. The corresponding sulfone (i.e., a compound 2 wherein n is 2) is obtained, if desired, by subsequent reaction with an oxidant such as metachloroperbenzoic acid (MCPBA) in a suitable solvent such as dichloromethane (DCM) at 0xc2x0 C. or ambient temperature, or using hydrogen peroxide in acidic acid; preferably, this reaction is performed with potassium peroxymonosulfate (Oxone(copyright)) in an organic solvent, preferably DMF, or in a mixture of water and water-miscible organic solvents such as methanol, DMF or the combination of two, at ambient temperature or under moderate heating. Alternatively, a compound 2 wherein n is 2 can be obtained from compound 1 directly, by reaction with the appropriate arylsulfinate. Preferably, the sulfinate is obtained and used as the sodium salt, or as the salt with a tertiary organic amine such as N-methylmorpholine (NMM). The sodium arylsulfinate can be conveniently obtained by reaction of the appropriate aryl-sulfonyl chloride with sodium iodide in acetone, preferably at ambient temperature, and it is isolated before reaction with compound 1, which takes place in a suitable solvent such as toluene in the absence or presence of a suitable base such as sodium bicarbonate, at a temperature ranging from 25xc2x0 C. to reflux. The salt with NMM is obtained by reaction of the arylsulfonyl chloride with 4-thiocresol and NMM in DCM, preferably at a temperature ranging from xe2x88x9250 to xe2x88x9278xc2x0 C., and it is reacted in situ with compound 1, then raising the temperature up to 25xc2x0 C. or reflux.
A compound 4 can be obtained from the corresponding compound 2 by conjugate addition of a reagent of formula R2H, or a salt thereof, where R2 is as defined previously. Thus, when R2 is a group xe2x80x94Sxe2x80x94Ar, xe2x80x94S-Het, xe2x80x94Sxe2x80x94CH2xe2x80x94Ar or xe2x80x94Sxe2x80x94CH2-Het, the reagent is the corresponding thiol, or a salt thereof; when R2 is Oxe2x80x94Ar, the reagent is the corresponding aromatic carbinol; when R2 is 2,5-dioxo-1-imidazolidinyl or a substituted derivative thereof, the reagent is the corresponding 2,4-imidazolidinedione. Said conversion from a compound 2 into a compound 4 can be accomplished, under identical or similar conditions, either when n in 2 is zero or it is 2; however, the preparation of compounds of formula (I) wherein R2 is sulfanyl is better performed from compounds 2 where n is 2, because otherwise it is difficult to discriminate between the two sulfur atoms in the following oxidative step. Typically, the conjugate addition of said mercaptans and aromatic carbinols to a compound of formula 2 is accomplished using the reagents neat, or in a suitable organic solvent such as DCM, DMN, toluene, tetrahydrofuran (THF), acetonitrile (MeCN), methanol or ethanol, at temperatures ranging from ambient to reflux, in the absence or presence of a suitable base such as sodium bicarbonate, sodium carbonate, TEA, sodium methoxide or sodium ethoxide, preferably under a nitrogen blanket. When the reagent is 2,4-imidazolidinedione or a substituted derivative thereof, the conjugate addition to a compound 2 is preferably performed in toluene or DMF in the presence of a suitable base such as sodium bicarbonate, TEA, NMM and the like, at a temperature ranging from ambient to reflux, preferably between 50 and 110xc2x0 C.; alternatively, a preformed salt of said reagent can be used, especially sodium, potassium and lithium salts, which can be obtained by treatment with suitable strong bases, especially sodium hydride, potassium hexamethyldisilazide, potassium tert-butoxide and butyllithium, in a suitable organic solvent.
When a compound 4 where n is zero is obtained by the methods above, it may be converted, if desired, into the corresponding compound where n is 2 by oxidation, under the same conditions described previously for the oxidation of a compound 2 where n is zero to a compound where n is 2.
Alternatively, a compound 4 can be obtained from a compound 1 through the intermediacy of a compound 3. This alternative route provides advantages when the reagent R2H is reluctant to the conjugate addition to a compound 2, e.g. when R2H is 2,5-dioxo-1-imidazolidine, and particularly when it is 4,4-dimethyl-2,5-dioxo-1-imidazolidine and the N-alkyl derivatives thereof. In the first step, said reagent R2H is condensed with the bromomethylacrylate 1 to provide 3. Typically, the reaction is performed in a solvent such as DMF or toluene, at temperatures ranging from 50xc2x0 C. to reflux, and preferably in the presence of sodium bicarbonate. In the following step, conjugate addition of the suitable aryl-thiol to the intermediate 3 provides a compound 4 where n is zero. This reaction can be performed under the same conditions described above for reaction of 2 with a mercaptane R2H to provide 4.
Compounds 4 where R is a hydrogen atom and n is 2 are specifically represented by structure 5 and as such are a first object of this invention, i.e. the compounds of formula (I) wherein X is hydroxy (the xe2x80x98carboxylatesxe2x80x99). Compounds 4 where R is the residue of a carboxylic ester, as defined previously, and n is 2, are converted to said final compounds 5 by hydrolysis, according to the general methods known in the art such as using 6N HCl in acetic acid and refluxing for 10 to 20 hours or using iodotrimethylsilane in chloroform. When the R group is benzyl and R2 is not a sulfanyl residue, a preferred method to obtain the free acid is hydrogenolysis, especially in the presence of a palladium catalyst such as Pd on charcoal, in an inert organic solvent such as ethanol or DMF or the like, typically at room temperature and under atmospheric pressure or moderate pressure. When the R group is tert-butyl, a preferred method for obtaining the free acid is reaction with HCl or trifluoroacetic acid, in inert organic solvents such as DCM, THF, MeCN and the like, optionally in admixture with water, methanol or ethanol, at temperatures ranging from xe2x88x9220 to +40xc2x0 C.
Compounds 4 where R is the residue of a carboxylic ester and n is zero are converted to compounds 5 by a two-step procedure involving oxidation and hydrolysis, or hydrolysis and oxidation, as preferred. Conditions for oxidation and hydrolysis are the same as described above.
Compounds 4 where R is a hydrogen atom and n is 2, which have structure 5, are converted to compounds 6, which specifically represent the second object of this invention, i.e. structure (1) wherein X is xe2x80x94NHOH (the xe2x80x98hydroxamatesxe2x80x99), by activation of the acid and coupling with hydroxylamine or an O-protected derivative thereof. This reaction can be performed by several routes well known to those skilled in the art. For example, the acid can be activated as its chloride or a mixed anhydride. A preferred method for activation as the acid chloride is reaction with oxalyl chloride, typically in DCM containing DMF as a catalyst, at 0xc2x0 C. to ambient temperature. A preferred method for activation as a mixed anhydride is reaction with a chlorocarbonate such as chloroethylformate in anhydrous TBF or a similar compatible solvent, in the presence of a tertiary amine such as TEA, NMM and the like. Alternatively, the acid can be activated by a carbodiimide condensing agent such as dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSCDI, water soluble carbodiimide), preferably in the presence of 1-hydroxybenzotriazole (HOBt) in an inert organic solvent such as DNEF at 0xc2x0 C. to room temperature. Another method for the activation of the acids of formula 4 where R is hydrogen is reaction with benzotriazolyl-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) in a suitable organic solvent such as MeCN, THF or DCM in the presence of a tertiary amine such as TEA or NMM. A further method is reaction with O-benzotriazolyl-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (HBTU) or O-benzotriazolyl-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate (TMTU), under conditions similar to those described for the BOP reagent. When the activation is performed with oxalyl chloride, the acid chloride is usually isolated crude before reaction with the hydroxylamine reagent; when with chloroethylformate, EDC or WSCDI, the hydroxylamine reagent is preferably added after about 1 hour at room temperature; when with the BOP reagent, HBTU or TBTU, the hydroxylamine reagent is O-protected and it is preferably added from the beginning. Suitable O-protected hydroxylamines are O-(benxyl)benzylhydroxylamine, O-(tert-butyl)hydroxylamine, O-(tetrahydropyranyl)hydroxylamine, O-(trimethylsilyl)hydroxylamine and O-(tert-butyldimethylsilyl)-hydroxylamine, the first two being preferably used as their hydrochlorides and freed in situ by a tertiary amine such as TEA or NMM. Alternatively, when activation of the acid is performed with oxalyl chloride or WSCDI, the unprotected hydroxylamine (e.g., as the commercial 50% solution in water) or the hydrochloride thereof can be used, either in the organic solvents specified above or after dissolution in water or in a mixture of water and THF. Suitable conditions for the condensation step vary according to the activation method. Typically, when activation is by the acid chloride method, the reaction is fast and is complete within 1-5 hours at temperatures ranging from 0xc2x0 C. to 25xc2x0 C.; otherwise it can be slower, usually requiring stirring overnight at ambient temperature or even 1-5 days. When an O-protected hydroxylamine is used in the condensation, the reaction affords O-protected hydroxamate derivatives, and the desired free-hydroxamates 6 are obtained after removal of the protecting group. In particular, when O-(benzyl)hydroxylamine is used, deprotection is performed by hydrogenolysis, preferably with a palladium catalyst such as 5% Pd on charcoal, 5% Pd on BaSO4, or palladium hydroxide on carbon (Pearlman""s catalyst), typically in methanol or ethanol. When O-(tert-butyl)hydroxylamine is used, the free hydroxamate can be obtained after treatment with neat or aqueous trifluoroacetic acid, or with HCl in DCM. When O-(tetrahydropyranyl)hydroxylamine is used, the free hydroxamate is rapidly obtained by reaction with 4N aqueous HCl in suitable organic solvents or mixtures thereof, e.g. dioxane and methanol. When O-(trimethylsilyl)hydroxylamine is used, deprotection is usually achieved during work up, e.g. by partitioning of the condensation mixture between ethyl acetate and diluted hydrochloric acid. When O-(tert-butyldimethylsilyl)hydroxylamine is used, deprotection can be achieved by HF or fluoride salts, preferably with tetrabutylammonium fluoride, in a suitable organic solvent such as THF, at temperatures ranging from xe2x88x9210 to +25xc2x0 C.
Compounds 4 where R is a hydrogen atom and n is zero are converted to compounds 6 by a sequence involving oxidation at the sulfur atom, activation of the carboxy group, condensation of the activated carboxy group with hydroxylamine or an O-protected derivative thereof and, when required, unmasking of the free hydroxamic group. The oxidation can be performed first, i.e. on said compounds of formula 4, as described previously for the oxidation of a compound of formula 2 where n is zero to the corresponding compound where n is 2. Alternatively, the oxidation can be performed at a later stage, i.e. on the O-protected or free hydroxamic acid, in which case a preferred oxidant is oxone, in a suitable organic solvent such as DMF, mixture of water and one or two water miscible organic solvents, such as methanol, ethanol, DMF and THF, at a temperature ranging from 5 to 25xc2x0 C. Conditions for the other steps of the sequence, i.e. activation of the carboxy group, coupling with hydroxylamine or a protected derivative thereof and, if required, deprotection, are the same as described previously. 
In some cases, minor modifications of the general procedure indicated in Scheme I can be used to obtain compounds 4. For example, conversion of a compound 2 into a compound 4 wherein R2 is a sulfanyl residue can be achieved in two steps, the first involving addition of HBr to a compound 2 to obtain the bromomethyl derivative, which is then reacted with the thiol which R2H can represent. This two-step procedure can be convenient for less reactive thiols, in particular when R2 is SCH2xe2x80x94Ar or xe2x80x94Sxe2x80x94CH2-Het. A preferred solvent for the addition of HBr to a compound 2 is acetic acid, usually at ambient temperature. The thiol is preferably reacted with said bromomethyl intermediate in the presence on an organic or inorganic base such as TEA, NMM, sodium bicarbonate, potassium carbonate and the like. Less reactive thiols can be advantageously reacted after conversion to salts thereof, e.g. by treatment with potassium hexamethyldisilazide at low temperature in a suitable organic solvent such as THF, and reacted in situ with the compound 2. The bromomethyl intermediate, or the corresponding carbinol, can also be used to obtain compounds 4 wherein R2 is 2,5-dioxo-1-imidazolidinyl. In particular, the bromomethyl derivative can be reacted with 2,4-imidazolidinedione, or a derivative thereof, under conditions similar to that described above for reaction with a thiol, and the carbinol can be condensed with the same reagent under Mitsunobu conditions, i.e. in the presence of triphenylphosphine and diethyl azodicarboxylate in DMF a temperatures ranging from 0 to 25xc2x0 C.
The compounds of formula (I) wherein R2 is 2,4-dioxo-1-imidazolidinyl can be obtained by the variant described in Scheme II below. As therein outlined, an aminoacid H2Nxe2x80x94CHR3xe2x80x94COOH where R3 is a hydrogen atom, C1-4 straight or branched alkyl or benzyl, or a salt or an ester thereof, especially the methyl or ethyl esters, is condensed with is compound 1, as defined in Scheme I, to obtain a compound 7 where R, R3 are as above defined, and Rxe2x80x2 is either a hydrogen atom or methyl or ethyl. This reaction is carried out in a suitable organic solvent, with or without a base, at temperatures ranging from 0 to 50xc2x0 C., preferably around ambient temperature. A preferred solvent is DMF; preferred bases, which can be present in amounts variable to a catalytic one to 3 molar equivalents, are tertiary amines, such as TEA, NMM, Hunig""s base and the like. The obtained compound 7 is then reacted with sodium or potassium cyanate, or with an isocyanate of formula R4xe2x80x94NCO where R4 is C1-4 alkyl, phenyl or benzyl, to obtain an intermediate urea, which is cyclized to a compound 8 where R, R3 and R4 are as defined above, in a suitable organic solvent such as THF, dioxane, MeCN, DMF and the like, at temperatures ranging from about 20xc2x0 C. to reflux. Said compound 8 is then reacted with an aryl thiol of formula R1xe2x80x94C6H4xe2x80x94SH to obtain a compound 9 where R1 is as above defined and n is zero. Typically, the conjugate addition of said aryl thiol to a compound 8 is accomplished in a suitable organic solvent such as DCM, DMF, toluene, tetrahydrofuran (THF), acetonitrile (MeCN), methanol or ethanol, at temperatures ranging from ambient to reflux, in the absence or presence of a suitable base such as sodium bicarbonate, sodium carbonate, TEA, sodium methoxide or sodium ethoxide, preferably under a nitrogen blanket. Conversion of a compound 9 where n is zero into a compound 9 where n is 2 is accomplished under the conditions previously described in Scheme I, preferably with Oxone(copyright) in an organic solvent such as DUF or in a mixture of water and water-miscible organic solvent such as methanol, DMF or the combination of two, at ambient temperature or under moderate heating. Alternatively, the same synthetic sequence is carried out on a compound 2, as defined in Scheme I, to obtain the same compound 9 via 10. Compounds 9 where n is two and R is a hydrogen atom are the desidered compounds of formula (I) where X is HOxe2x80x94 and R2 is 2,4-dioxoimidazolidin-1-yl. The corresponding compounds of formula (I) where X is HONHxe2x80x94 are obtained, if desired, as described previously (Scheme I) for the conversion of a compound 5 into a compound 6. 
When required or convenient, chemical modifications of the group R1 or R2 in intermediates 2, 3, 4 and 9 can be performed in the above processes to obtain the final compounds of formula (I). For example, a compound 3 or 4 wherein R2 is 2,5-dioxo-1-imidazolidinyl having the 3-nitrogen atom unsubstituted can be alkylated at said atom to obtain the corresponding N-alkyl derivatives, e.g. with methyl iodide in DMF in the presence of potassium carbonate. When R1 and R2 in the final compounds of formula (I) are, or contain, a reactive functional group, e.g. amino and hydroxy, these groups can be protected at the appropriate stage and unmasked when convenient, according to conventional methods well known in the art.
The chemistry in Scheme I and II proceeds through achiral or racemic intermediates, unless a substituent in R1 or R2 is chiral and enantiopure, or the aminoacid used in Scheme I for the preparation of compound 7 or 10 is chiral and enantiopure. When desired, pure enantiomers of the final products, in particular compounds of formula (Ixe2x80x2) above, may be obtained from racemic compounds (I), or racemic intermediates thereof, by methods well known to one skilled in the art. For example, racemic carboxylates, including compounds (I) where X is HOxe2x80x94 and intermediates 4, 9 where R is a hydrogen atom and n is zero, or intermediates 10 where R is a hydrogen atom, can be resolved by chiral salt formation, for example with enantiopure 1-phenylethylamine, brucine, ephedrine, strychnine, morphine. Alternatively, final racemic compounds or racemic intermediates can be resolved by chiral chromatography. By another method, carboxylic esters, preferably methyl, ethyl and butyl esters, can be selectively hydrolysed to chiral acids by lipases and esterases. By a still different procedure, racemic carboxylic acids can be converted to diastereomeric esters with chiral alcohols such as borneol, menthol and the like, which are then separated by crystallization or conventional chromatography. Alternatively, when in the acrylates of formula 2, 3, 8 in Schemes I and II R is the residue of a chiral alcohol such as bomeol, menthol and the like, diastereomeric compounds 4, 9 10 are obtained, and variable degrees of diastereoselectivity can be achieved.
The present invention further provides a compound of formula (I) as defined above for use in a method of treatment or prophylaxis of a disease mediated in a mammal by a matrix metalloproteinase, especially the gelatinases (MMP-2 and MMP-2), the membrane-type M involved in gelatinase activation (MMP-14), the stromelysins (MMP-3 and MMP-10), collagenase-3 (MMP-13) and neutrophyl collagenase (MMP-8). Diseases for which the compounds of the present invention are particularly intended are: tumor growth and metastasis; rheumatoid arthritis and osteoarthritis; ophthalmic diseases, in particular age-related macular degeneration and diabetic retinopathy; cardiovascular diseases, in particular restenosis; periodontal diseases; multiple sclerosis; Alzheimer disease.
The compounds of the present invention are typically administered in the form of pharmaceutical compositions, which can be prepared by combining the compounds of formula (I) or (Ixe2x80x2) or salts or hydrates or solvates thereof with a solid or liquid pharmaceutically acceptable career, and, optionally, with pharmaceutically acceptable adjuvants and excipients, employing standard and conventional techniques. In particular, said compounds can be administered:
a) orally, for example, as tablets, coated tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is present as such, or mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpynolidone gum tragacanth and gum acacia; dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The said aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin. Oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions The oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents;
b) parenterally, either subcutaneously, or intravenously, or intramuscularly, or intrastemally, or by infusion techniques, in the form of sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to the known art using those suitable dispersing of wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition fatty acids such as oleic acid find use in the preparation of injectables;
c) topically, in the form of creams, ointments, jellies, plasters, collyriums, solutions or suspensions;
d) rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
The compounds of this invention are advantageously administered orally in solid and liquid dosage forms. Daily dosages can vary within wide limits and will be adjusted to the individual requirements in each particular case. As a rule of thumb, a compound of formula (I) or (Ixe2x80x2) is advantageously administered at a dosage and frequency to achieve and maintain, for the whole period of therapy, a blood level in free drug (i.e., not bound to plasma proteins) ranging from about 1 to about 100 times its Ki against the most relevant MMP for the particular disease state, e.g. MMP-2 for cancer. Thus, the daily dose may be divided into multiple doses for administration, e.g. two to four times per day, which is generally expedient for compounds of formula (I) or (Ixe2x80x2) wherein X is HOxe2x80x94NHxe2x80x94; or, in the case of particularly favorable pharmacokinetics, which can be found in compounds of formula (I) or (Ixe2x80x2) wherein X is HOxe2x80x94, the drug can be given daily, or even at alternate days. Generally, an amount of the active compound effective in adult patients will be in the range of 1 to about 500 mg, but it is to be understood that such range may be exceeded depending on the particular compound being used, the severity of the disease being treated, and the requirement of the patient.
The compounds of the present invention and their preparation will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.